Oral bioavailability of ospemifene improves with food intake

Koskimies, Pasi; Katila, Kirsi; Lammintausta, Risto; Aaltonen, Anne-Mari; Vuorinen, Jouni; Saarni, Outi; Scheinin, Mika

doi:10.5414/cp201873

Cited by 9 publications

(5 citation statements)

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“…Because of the randomized sequence of treatments, this finding would not be confounded by the disease progression or other factors influencing the homeostasis over time between the two treatments. The decrease in PK parameter variability (CV%) with food has been previously reported (eg, ospemifene and telaprevir). In a related exploratory analysis, increase in vemurafenib exposure after food intake was greater among certain patients with lower fasted exposure than among the patients who had higher fasted exposures.…”

Section: Discussionsupporting

confidence: 55%

Section: Discussionmentioning

confidence: 96%

“…On Day 1 of each study period, samples were collected before dose and at 1,2,3,4,5,6,7,8,10,12,16,24,36,48,72,96,144,192, and 240 hours after dose. The human plasma concentrations of vemurafenib were determined by validated high-performance liquid chromatography tandem mass spectrometry (HPLC/MS/MS).…”

Section: Pharmacokinetic Sampling and Assessmentmentioning

confidence: 99%

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The effects of a high-fat meal on single-dose vemurafenib pharmacokinetics

Ribas

Zhang

Chang³

et al. 2014

The Journal of Clinical Pharmacology

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Vemurafenib is an orally bioavailable BRAF inhibitor approved for the treatment of BRAF(V600) -mutant metastatic melanoma. It is important to understand the effects of a high-fat meal on the pharmacokinetics (PK) of vemurafenib in humans because it is a Biopharmaceutics Classification System Class IV drug and its PK can be altered by food. An open-label, multicenter, randomized, 2-period crossover study was performed to evaluate the effect of food (high-fat meal) on the PK of a single oral dose of vemurafenib. Secondary objectives were safety and tolerability, efficacy with best overall response rate, and overall survival during the treatment period. The concomitant intake of food (high-fat meal) increased mean Cmax 3.5 to 7.5 µg/mL and mean AUC0-∞ 119 to 360 µg·h/mL after a single 960 mg dose of vemurafenib (N = 13-15 patients). An effect of food on single-dose exposure is suggested by point estimates and 90% CI of geometric mean ratios for vemurafenib plasma AUC0-∞ (4.7) and Cmax (2.5). Toxicity and response rate of vemurafenib in this study were consistent with prior experience in patients with BRAF(V600) -mutant metastatic melanoma. A high-fat meal increased the exposure to vemurafenib without altering the mean terminal half-life.

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Section: Discussionsupporting

confidence: 55%

Section: Discussionmentioning

confidence: 96%

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The effects of a high-fat meal on single-dose vemurafenib pharmacokinetics

Ribas

Zhang

Chang³

et al. 2014

The Journal of Clinical Pharmacology

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“… 25 – 27 A separate Phase I study conducted to assess the effect of food on the oral bioavailability of ospemifene showed that administration of the drug with food increased both maximum concentration and area under the concentration–time curve by two to three times that seen when given in the fasted state. 30 In addition to standard safety laboratory assessments and adverse event monitoring, endometrial safety was thoroughly monitored by measuring endometrial thickening, histologic examination of endometrial biopsies, and Ki-67 staining to evaluate endometrial proliferation. 26 Potential efficacy markers assessed in this study included serum lipids (low-density lipoprotein, high-density lipoprotein, total cholesterol, and triglycerides) and vascular markers to evaluate cardiovascular disease treatment potential, 27 serum and urinary bone markers to assess bone turnover, 25 vaginal maturation index to assess the potential treatment of VVA, and the Kupperman index to assess the potential treatment of menopausal symptoms.…”

Section: Clinical Studiesmentioning

confidence: 99%

Safety and efficacy of ospemifene for the treatment of dyspareunia associated with vulvar and vaginal atrophy due to menopause

Wurz¹,

Kao²,

DeGregorio³

2014

CIA

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During the menopausal transition, women experience a number of symptoms due to declining estrogen levels, including vasomotor symptoms and vulvar and vaginal atrophy (VVA). Unlike vasomotor symptoms, vaginal dryness and dyspareunia, the main symptoms of VVA, typically worsen without treatment and can significantly impact the quality of life. Up to 60% of postmenopausal women may be affected by VVA, but many women unfortunately do not seek treatment due to embarrassment or other factors. After 20+ years in development, ospemifene (Osphena™) was approved by the US Food and Drug Administration in 2013 for treatment of moderate-to-severe dyspareunia associated with VVA due to menopause. As the first non-hormonal alternative to estrogen-based products for this indication, the approval of ospemifene represents a significant milestone in postmenopausal women’s health. Ospemifene is a non-steroidal estrogen receptor agonist/antagonist, also known as a selective estrogen receptor modulator (SERM), from the same chemical class as the breast cancer drugs tamoxifen and toremifene. Unlike other selective estrogen receptor modulators, ospemifene exerts a strong, nearly full estrogen agonist effect in the vaginal epithelium, making it well suited for the treatment of dyspareunia in postmenopausal women. Results of Phase III clinical trials showed that ospemifene significantly improved the vaginal maturation index (decreased parabasal cells and increased superficial cells), decreased vaginal pH, and decreased severity of the self-identified most bothersome symptom (dyspareunia or vaginal dryness) compared to placebo. Long-term safety studies revealed that 60 mg ospemifene given daily for 52 weeks was well tolerated and was not associated with any endometrium or breast-related safety concerns. This review discusses the preclinical and clinical data supporting the use of ospemifene for the treatment of dyspareunia associated with VVA due to menopause and provides an overview of its clinical safety.

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“…Die Resorption ist bei Einnahme mit dem Essen am besten [38]. Im Plasma ist Ospemifen zum größten Teil an Eiweiß gebunden [39].…”

Section: Phase-i-studienunclassified

Selective estrogen receptor modulators (SERM)

Stute

Birkhäuser

2015

Gynäkologische Endokrinologie

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Die Suche nach der idealen Substanz für die Behandlung von Östrogen-bzw. Östrogenmangel-assoziierten Symptomen und Erkrankungen ist nicht neu. Bereits in den 1930er-Jahren wurden die ersten selektiven Östrogenrezeptormodulatoren (SERM) entwickelt, die die gewünschten Östrogeneffekte, aber nicht deren Nachteile besitzen. Damit sind sowohl Östrogen-als auch Antiöstrogeneffekte der SERM gemeint. Die potenziellen Indikationsgebiete schienen und scheinen dabei riesig zu sein und reichen von der Therapie des Mammakarzinoms und der Osteoporose über die Kontrazeption bis zur Kinderwunschtherapie. WirkmechanismusÖstrogene üben ihre biologische Funktion rezeptorvermittelt über die Östrogenrezeptoren α (ERa) und β (ERb) aus. ER binden entweder als Homodimere (ERa/ERa bzw. ERb/ERb) oder Heterodimere (ERa/ERb) an spezifische DNA-Abschnitte, welche "estrogen response elements" (ERE) enthalten. Alternativ binden sie als Monomere (ERa, ERb) an von AP1-Elementen kontrollierte Genabschnitte und aktivieren deren Transkription. Dem klassischen ER-vermittelten steht der nichtgenomische Regulationsmechanismus gegenüber: Hierbei wird indirekt die Transkription bestimmter Genabschnitte aktiviert, ohne dass eine DNA-Bindung der ER erfolgt [1].

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Oral bioavailability of ospemifene improves with food intake

Cited by 9 publications

References 0 publications

The effects of a high-fat meal on single-dose vemurafenib pharmacokinetics

The effects of a high-fat meal on single-dose vemurafenib pharmacokinetics

Safety and efficacy of ospemifene for the treatment of dyspareunia associated with vulvar and vaginal atrophy due to menopause

Selective estrogen receptor modulators (SERM)

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